Genes That Make Us Humans: Disease Mutation

Notch2NL isn't the only example where genes have been duplicated in humans. Scientists have identified more than 30 gene duplications that are unique to our species. Some believe these duplications could be responsible for some of our uniquely human traits.

For instance in 2012, researchers at Columbia's Zuckerman Institute discovered that humans have a unique, duplicated form of the SRGAP gene, which they named SRGAP2C.

SRGAP genes play a crucial role in controlling the number of connections, known as synapses, that a neuron makes with its neighbouring cells. The more synapses a neuron has, the more information it can process. The new, human-specific SRGAP2C gene essentially allows humans to form more synapses, and stronger and denser connections between neurons.

Although they may explain our species' unmatched brainpower, gene duplications such as those that resulted in SRGAP2C and Notch2NL may have left us vulnerable to developing neuropsychiatric disorders. For instance, mutations in the region of the genome where Notch2NL is found are associated with a range of neurodevelopmental disorders, including ADHD, schizophrenia, autism spectrum disorder, and intellectual disability, according to Salama and colleagues.

"If you want to make more of a gene, a really easy way to do it is copy and duplicate the gene so there are multiple copies that can all be turned on at once," says Tony Capra, professor of epidemiology and biostatistics at the University of California, San Francisco.

"But of course, once you have that more complex control there are more ways it can go wrong."

For instance, if the sequence in the newly copied gene is very similar to its predecessor, it can sometimes confuse the machinery that makes copies of our genomes, leading to genes being moved around, inserted in different places, or combined in different, maladaptive ways. Duplicated genes also contain repetitive sequences that make them more prone to additional deletions and duplications.

It's also possible that some of the "genes that made us human" may be in areas of the genome that are prone to high mutation rates, making us susceptible to disease. In a 2022 study, Craig Lowe, professor of molecular genetics and microbiology at Duke University, analysed the human genome to find the places that had changed the most since our ancestors diverged from chimpanzees. He found that many of the regions – known as Haqers ("human ancestor quickly evolved regions") – were involved in regulating the developing brain, for example by inducing the growth of more neurons.

These regions also tended to be in areas with high mutation rates, which, according to Lowe, could lead to problems further down the evolutionary branch.

"These quickly mutating regions of the genome are like evolution's cauldron – the places where everything comes together and gets mixed up," says Lowe.

Lowe found that mutations in many Haqers he discovered are associated with schizophrenia and bipolar disorder.

It's possible such genes now making us ill because evolutionary trade-offs are pulling our bodies in different directions. Our risk of developing cancer seems to be inversely related to our risk of developing Alzheimer's, Parkinson's and Huntington's disease. Cancer involves the uncontrolled growth of new cells, while these diseases are linked to cell death.

It's also true that it is often the most recently evolved regions that are often vulnerable to dysfunction, suggesting that we might not have had time to evolve compensatory buffers to protect ourselves.

Alternatively, it could be that the environment we now find ourselves living in is very different to that of our ancestors.

"We have been able to change and remodel our environments so quickly, and often much more quickly than the evolutionary process can keep up with," says Capra.

"This could create an evolutionary mismatch where adaptations that have been shaped over tens of thousands of years are no longer suited to our modern lives."

It's possible that understanding how certain genes lead to diseases could help inspire new treatments. Some even say it could even help us move towards a new era of personalised, precision medicine: where targeted drugs could be used for each unique genetic profile. However, others are more cautious.

"I think evolution is a really useful lens in which to view what goes wrong, and when, how and why," says Capra.

"But the major driver of variation in disease occurrence across humans is whether people have access to healthcare, healthy food, and clean water – those are the places I think we should be focusing efforts first."

- Author: Jasmin Fox-Skelly, BBC


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